Parkinson's disease (PD) is characterized by slowed movement, rigidity, and resting tremors resulting from progressive degeneration of dopaminergic neurons in the substantia nigra. Though there has been progress in identifying genetic causes of this disease, genetic mutations only account for 5-10% of PD cases. Thus, our lab is interested in pursuing the interaction between genetic susceptibility and environmental insults. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamine neurotransmitters into vesicles in cells affected by PD, allowing for rapid synaptic release. VMAT2 also provides protection from the effects of the breakdown of these transmitters inside the cell and from environmental toxicants. Our lab has previously characterized a mouse model with a 95% reduction in VMAT2. These mice show progressive cell death of the dopamine neurons of the substantia nigra, a-synuclein accumulation, and both motor and non-motor symptoms of PD. As VMAT2 levels or function may be key in mediating susceptibility to this disease, it is possible that increased VMAT2 levels could have therapeutic benefit in PD. We have developed a transgenic mouse that overexpresses VMAT2. These mice have twice as much VMAT2 and vesicular dopamine uptake as wildtype mice and improved outcomes on measures of anxiety and depressive behavior. These preliminary data suggest that the VMAT2-HI mice show a phenotype opposite of the VMAT2-LO mice with resistance to the parkinsonian state. The goal of this proposal is to examine the potential for elevated VMAT2 levels to rescue parkinsonian phenotypes. This study will examine the pathological and behavioral effects of varying VMAT2 levels in our mice following 1) an acute administration of the toxicant MPTP and 2) viral vector- mediated overexpression of A53T a-synuclein. This proposal will show if increased VMAT2 levels are able to decrease the severity of PD symptoms. Completion of the proposed studies will reveal interaction between VMAT2 level and severity of PD symptoms and highlight the therapeutic potential of VMAT2 modulation by drugs.